The present invention relates generally to a penetration enhancing transdermal composition and related method of use. The penetration enhancer is a functional derivative of a fatty acid. The functional derivative minimizes the acid catalyzed degradation of acid-labile drugs.
Transdermal drug delivery systems are effective means for introducing drugs into the bloodstream by applying them to skin or mucosa. Advantages of transdermal delivery include convenience, comfort, avoidance of the risks associated with enteral and parenteral administration and control over drug absorption. It is particularly suitable for treating conditions which are systemic in nature, and can be used with any drugs that can pass through the skin or mucosa and do not irritate, or cause an allergic reaction at the site of application. Permeability of a drug through the skin may be affected by the stratum corneum, which is characterized by dehydrated and keratinized cells, or by the epidermal layer in the mucosa. The art has recognized that the barriers to the transdermal or percutaneous delivery of drug through the skin can be overcome or reduced by using particular vehicles and carriers into which the drug is incorporated so that the vehicle or carrier can remain at the site of application and increases the drug's penetration at a particular site.
U.S. Pat. No. 4,863,970 by Patel (1989) discloses improved compositions and methods for improving the penetration of a broad category of pharmaceutically-active agents which are lipophilic or hydrophilic, including salts thereof, and which produce little or no skin irritation to human or animal tissue systems. The invention provides penetrating topical compositions based on the use of a pharmaceutically-active agent dissolved in, or admixed with, a penetration-enhancing binary mixture of (a) about 1 to 95% by weight of one or more cell-envelope disordering compounds selected from the group consisting of oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate and glycerol trioleate and mixtures thereof and (b) 5-75%, and preferably 5-49%, by weight of a C2 or C3 lower alcohol. In addition, the formulation can optionally contain 0 to 45% by weight of inert ingredients which are soluble within the enhancer composition. Such ingredients can vary from hydrophilic to hydrophobic depending upon the desired combination. Representative inert ingredients include water, polypropylene glycol, polyethylene glycol, polyvinyl alcohols, polyvinylpyrrolidone, mineral oil, silicone oil, ethylene-vinyl acetate polymers or other low molecular weight polymers soluble in water, lower alcohols or suitable oils. This patent does not suggest the particular suitability of functional derivatives of fatty acids in stabilizing drugs subject to acid catalyzed degradation, as well as in functioning as penetration enhancers.
U.S. Pat. No. 5,162,315 describes the use of certain substituted alkanamides as penetration enhancers, but does not suggest their particular suitability with acid labile drugs.
Cooper, E., "Increased Skin Permeability for Lipophilic Molecules" J. Pharm. Sci. 73: (Aug. 1984) discloses the use of oleic acid in different concentrations in the presence of propylene glycol as a solid and in the presence of 1,1-butanediol.
Schering AG EPO patent publication No. 573, 133 discloses a combination of gestodene and penetration enhancing agents, generally, including isopropyl myristate.
Although penetration enhancers are well-known in the art, problems associated with combining certain penetration enhancers with certain drugs in transdermal compositions have not been addressed. For instance, applicant has observed that oleic acid, which is a commonly used penetration enhancer, will react with certain drugs, not only causing them to degrade but also creating by-products that interfere with drug penetration and delivery. Applicant has discovered that in order to overcome this type of problem, functional derivatives of fatty acids can be used in transdermal formulations containing drugs that degrade in the presence of weak organic acids, such as oleic acid, particularly over prolonged periods of time, for example, for weeks or months during storage. Such drugs are referred to herein as "acid labile" drugs and include esters, .alpha.-, .beta. unsaturated ketones, 4-aminolevulinic acid, imines and similar compounds subject to degradation in the presence of weak organic acids, especially oleic acid. Applicant was the first to appreciate the above described problem and solution.
The term "fatty acid" is used here in the broadest sense to include saturated and unsaturated, straight and branched chain aliphatic acids having from four to twenty-four carbon atoms. The term "functional derivative" is used here to refer to isosteric modifications of fatty acids or to refer to non-acidic derivatives of the carboxylic functional group of a fatty acid or isosteric modifications thereof.